Project Summary Human respiratory syncytial virus (RSV) is recognized as the single most important viral cause of acute respiratory disease in infants and young children worldwide. Elderly populations and immunocompromised individuals are also at significant risk for serious RSV disease. Despite this very substantial disease burden imposed by RSV worldwide, there are no vaccines available. Several problems have impeded RSV vaccine development. First is safety. An early formalin-inactivated vaccine (FI-RSV) predisposed infants to more severe disease upon natural exposure to live virus resulting in concerns about the safety of all subsequently developed RSV vaccines, particularly nonreplicating vaccines. A second problem is a lack of understanding of requirements for stimulation protective responses making efficacy of new vaccine candidates difficult to predict. A third problem is the failure of RSV infections as well as many vaccine candidates to stimulate long-term, protective immune responses. This proposal is designed to test the hypothesis that novel virus-like particle (VLP) RSV vaccine candidates, unlike any previously tested, may be developed into an RSV vaccine. Published results indicate that Newcastle disease VLPs expressing RSV glycoproteins are very effective and safe vaccines that stimulate very durable protective responses in a murine system. This project will further develop these VLPs as RSV vaccine candidates. This project will test the hypothesis that different conformational forms of RSV F protein impact the properties of anti-RSV immune responses. The goal is to identify the conformation of RSV F protein, expressed on VLPs, that stimulate high titer neutralizing antibodies and protective, long-lived and memory immune responses and to test the efficacy and safety of selected vaccine candidates in cotton rats. Specific Aim 1: to determine neutralizing antibody titers and levels of protection from RSV challenge stimulated in mice by three different second generation VLP vaccine candidates. Specific Aim 2: to assess the safety afforded by selected VLPs after immunization of mice. Specific Aim 3: to assess the safety and protection afforded by a selected VLPs after immunization of cotton rats.